Delivery system for enhanced onset and increased potency

ABSTRACT

The invention discloses a swallow tablet which is capable of disintegrating within less than about fifteen minutes and providing fast delivery of therapeutic drugs. The delivery system is composed of between 0.250 and 1.0 Gm of an alkali metal or alkaline-earth metal salt of an edible organic acid. A preferred delivery system is trisodium citrate.

This is a division of application Ser. No. 07/908,527, filed on Jun. 29,1992, now U.S. Pat. No. 5,424,075.

FIELD OF THE INVENTION

The invention relates to a delivery system for therapeutic drugs whichmay be incorporated into a solid dosage form to provide a swallowabletablet. Specifically the invention relates to the use of salts of edibleorganic acids in combination with a therapeutic drug.

BACKGROUND OF THE INVENTION

Previously it has been shown that effervescent dosage forms may providefaster action for some drugs. This was often attributed to the fact thatsuch dosage forms were dissolved in water prior to ingestion andtherefor the drug was in solution and readily available for absorption.

However, the effervescent delivery system has been unsatisfactory forsome consumers; and can present formulators with difficult taste maskingproblems.

It has now been found that the fast delivery of an effervescent system,with an enhanced onset of action, may be provided in a solid oral dosageform as a swallowable tablet.

DESCRIPTION OF THE DRAWINGS

The Figures relate to Example 1 where ranitidine was administered todogs with a delivery system composed of trisodium citrate andbicarbonate.

FIG. 1 is a graph of the reduction in tritratable acidity (percent)versus time after dosing (minutes) comparing the activity of the soliddosage form ("DRY") and an effervescent dosage ("WET") of the sameconcentration (0.3 mg/kg) and the same acid neutralizing capacity of 16milliequivalents (mEq). The squares show the control dosage (i.e.without antacid).

FIG. 2 is a graph of the gastric acidity (pH) versus time after dosing(minutes) comparing the activity of the solid dosage form ("DRY") and aneffervescent dosage ("WET") of the same concentration (0.3 mg/kg) andthe same acid neutralizing capacity of 16 milliequivalents. The squaresshow the control dosage (i.e. without antacid) and the triangles showthe administration of water.

FIG. 3 is a graph of the gastric acidity (pH) versus time after dosing(minutes) of the solid dosage form ("DRY") showing the effect on dogs.

FIG. 4 is a graph of the reduction in tritratable acidity (percent)versus time after dosing (minutes) of the solid dosage form ("DRY")showing the effect on dogs.

SUMMARY OF THE INVENTION

The invention provides a delivery system for enhanced onset andincreased potency of therapeutic drugs. The delivery system plustherapeutic may be provided in a solid oral dosage form, such as aswallow tablet. The delivery system comprises an effective amount oftherapeutic drug and salt of an edible organic acid, wherein the salt ispresent in an amount of between 0.250 Gm and 1.0 Gm per tablet with atleast about 0.5 Gm salt per dose. The edible organic acid is chosen fromthe group consisting of citric, malic, fumaric, tartaric and succinicacid or mixtures thereof. The salt is an alkali metal salt or analkaline-earth metal salt or mixtures thereof. Therapeutic drugs ofparticular interest are chosen from the group consisting of analgesics,H₂ Blockers and sympathomimetic amine drugs. The delivery system ispreferably composed of trisodium citrate and may additionally contain acarbonate or bicarbonate.

DESCRIPTION OF THE INVENTION

The invention provides a solid oral dosage form which may be swallowed.The tablet will disintegrate in vivo within about fifteen minutes andprovide enhanced onset of action over previous solid oral dosage formson the order of the enhanced onset seen with the effervescent deliverysystem. It is speculated, though not relied on, that the delivery systemdisclosed herein provides rapid stomach emptying on the order of thatseen previously only with effervescent systems which are dissolved andingested as liquids. This rapid stomach emptying gets the active drug tothe site of absorption faster than previous solid dosage forms andtherefore provides for a more rapid onset of action and increasedpotency.

The delivery system is composed of a salt of an edible organic acid inan amount of at least about 0.5 Gm per dose. Practical limits on tabletsize means that a tablet could contain materials up to a total of about1.5 Gm, which must include the salt, active drug and all other materialsrequired for tabletting. A one tablet dose would contain from about 0.5GM to about 1.0 Gm acid salt. If two tablets are to provide a dose, asingle tablet could contain from about 0.25 Gm to about 1.0 Gm.

Edible organic acids useful in the invention are citric acid, malicacid, fumaric acid, tartaric acid, succinic acid and the like ormixtures thereof. Most preferred is citric acid. Useful salts includethe alkali metal salts and alkali-earth metal salts of these acids suchas sodium, potassium, calcium or magnesium or mixtures thereof. Apreferred salt is trisodium citrate.

The composition may also contain a carbonate or bicarbonate tofacilitate disintegration, or other such disintegrants. In addition,other excipients, useful in the art of tabletting, such as lubricants,binders, buffers, antioxidants, and colorants may be used. The tabletmay be coated with a thin layer of a protective coating to provide adustless and easily swallowed dosage form which is well known to thoseof skill in the art.

In addition to the delivery system and excipients, the solid dosage formwould contain an effective amount of an active drug substance. Thisamount may be the therapeutically effective amount commonly used inprescription dosage forms, or may, because of the efficacy of thedelivery system provided herein, be a reduced amount. Preferredtherapeutics include those from the classes of analgesics, H₂ Blockersand sympathomimetic amine drugs (commonly referred to as decongestants).

In particular, the dosage form is useful with analgesics chosen from thegroup consisting of aspirin, acetaminophen, ibuprofen and ketoprofen; H₂Blockers chosen from the group consisting of ranitidine, famotidine,cimetidine and nizatidine; and the sympathomimetic amine drugs chosenfrom the group consisting of phenylpropanolamine, phenylephrine andpseudoephridine. Because of the ability of this delivery system toprovide enhanced onset and increased potency (synergy), a lower dosethan that used with a prescription dosage in the traditional tabletforms presently available, may be used. Therefore, this swallow oraldosage form will be particularly useful for over-the-countermedications.

The composition may be provided as a capsule, tablet or caplet or othersolid oral dosage form.

A preferred method of preparing the granulate for the oral dosage formmay be used generally to prepare granulates of sodium salts of acidictherapeutic drugs of limited water solubility. The acidic therapeuticdrug of interest is mixed with anhydrous trisodium citrate to form a drymixture; to the dry mixture is added a near saturated aqueous solutionof trisodium citrate to form an overwet granulation mixture. A nearsaturated solution of trisodium citrate is approximately 40% by weighttrisodium citrate. An overwet mixture is a mixture that is wetter thancommonly used by those of skill in the art to prepare granulates. It maybe termed "more than damp" and is wet enough for a chemical reaction totake place between the citrate and the drug. An overwet mixture may bedescribed as doughy or may even approach a paste-like consistency. Theoverwet granulation mixture is then mixed for a time sufficient to allowthe anhydrous trisodium citrate to hydrate, forming a mixture dry enoughto granulate. The hydrated mixture is then granulated as is standard tothe art.

The following examples disclose preferred embodiments of the invention,but do not limit the applicability of the invention which is solelydefined by the claims.

EXAMPLES Example 1

Ranitidine

This study was designed to test the activity of a dry formulation ofEffervescent Antacid Base (EAB, described below) plus ranitidinecombination and to compare its effectiveness with that of the previouslytested wet formulations (those dissolved in water prior to ingestion).The combination of 0.3 mg/kg ranitidine+16 mEq EAB was selected fortesting.

Studies monitored gastric secretion in gastric fistula beagle dogs.Beagle dogs were dosed with two capsules containing (in total) 1.273 mgtrisodium citrate (2 H₂ O), 575 mg heat treated sodium bicarbonate plus0.3 mg/kg of the H₂ Blocker ranitidine (as per individual weight of eachBeagle). This dosage of ranitidine (administered without theeffervescent antacid base or sodium citrate) had been shown previouslyto be ineffective as an anti-secretory agent for such dogs. Altogether 8trials (8 dogs) were performed. In previous trials with "WET" dosageforms, ranitidine with the effervescent antacid base was dissolved andadministered to dogs via gastric fistula. In these trials, the testformulation was not dissolved in water and was not administered as asolution via the gastric fistula. Instead, for each dog, the appropriateamounts of dry ingredients were mixed and divided into two capsules. Thecapsules were given orally to the dogs and washed down by placing smallamounts of water on tongue via a syringe filled with 28 mL. About halfthe syringe content was used for washing down; content remaining wasadministered to dog via fistula. Thus, amounts of all constituentsincluding water, were the same as used in previous tests.

Results show that the effect of the two dosage forms is practicallyidentical. A comparison of the effects of the two formulations ontritratable acidity are presented in FIG. 1, and a comparison of theeffects on pH are presented in FIG. 2. Inspection of these figuresreveals that results of the present test with dry formulation, almostexactly duplicate the results of the previous tests with wetformulation. Within the limits of these tests, no significantdifferences between the two formulations can be discerned.

Because 2 of the 8 dogs tested received closed capsules instead of opencapsules, and because 3 of the dogs tested experienced vomiting duringthe test, the influence of these variables needed to be examined. Thus,the means for all dogs were compared to the means for only those dogswhich received closed capsules (FIG. 3), and were compared to the meansfor only those dogs which did not vomit (FIG. 4).

These comparisons reveal that, regardless of the variables of capsuleclosure or vomiting, the apparent equivalency of the two dosage formsremains definitely established.

The results showed that the ranitidine with the delivery system of theinvention was significantly more effective than would be expected from asolid oral dosage form (See FIG. 1-4). The figures demonstrate that asynergistic effect was produced when ranitidine, at an otherwiseineffective dose, combined with the delivery system utilized in theseexperiments and administered in a solid oral dosage form.

Similar results were obtained when ranitidine was administered toBeagles with a sodium citrate delivery system (not including a carbonateor bicarbonate).

Example 2

Acetaminophen Swallow Tablet Formulation

    ______________________________________                                        Formula 001                                                                                                Total                                            mg/tab  Ingredients          Quantities                                       ______________________________________                                        361.11  Acetaminophen 90% (Compap L)                                                                       108.33 Gm                                        648.11  Formula 169 (see below)                                                                            194.67 Gm                                        48.39   Sodium Starch Glycolate                                                                            14.52 Gm                                         0.10    Docusate Sodium, Sodium                                                                            0.03 Gm                                                  Benzoate (85:15)                                                      20.00   Crospovidone (Polyplasdone XL)                                                                     6.00 Gm                                          1.50    Magnesium Stearate   0.45 Gm                                          1080.00                      324.00 Gm                                        ______________________________________                                    

Pass all ingredients thru a #24 mesh screen to delump.

Add all together except the Magnesium Stearate and mix in a V-Blenderfor 7 minutes.

Add the Magnesium Stearate and blend for another 3 minutes.

Compress into tablets using 0.344"×0.750" capsule shaped tooling.

    ______________________________________                                        Formula 169                                                                                                Total                                            % W/W    Ingredients         Quantities                                       ______________________________________                                        7.0      Starch 1500         140 Gm                                           93.0     Trisodium Citrate Dihydrate                                                                       1860 Gm                                          100.0                        2000 Gm                                          ______________________________________                                    

Add powders to a 8 quart V-Blender with Intensifier Bar.

Dry mix with Intensifier Bar turned on for 3 minutes.

Wet granulate using 193 Gm of Water.

Discharge and pass thru a #24 mesh screen.

Dry in hot air oven at 130 F. overnight, (ca. 16 hours).

Dry size by passing thru a #24 mesh screen.

Example 3

Aspirin Swallow Tablet Formulation

    ______________________________________                                                                     Total                                            mg/tab  Ingredients          Quantities                                       ______________________________________                                        362.0   Aspirin & Starch Granulation 90%                                                                   72.4 Gm                                          700.0   Formula 169 (See Example 2)                                                                        140.0 Gm                                         50.0    Sodium Starch Glycolate                                                                            10.0 Gm                                          20.0    Crospovidone (Polyplasdone XL)                                                                     4.0 Gm                                           60.0    Formula 038*         12.0 Gm                                          18.0    Formula 171*         3.6 Gm                                           1210.0                       242.0 Gm                                         ______________________________________                                    

Dry Sodium Starch Glycolate and Crospovidone in hot air oven at 130° F.overnight, (ca. 16 hours).

Add all ingredients to a V-Blender and mix for ten minutes.

Compress into tablets using 0.344"×0.750" capsule shaped tooling.

    ______________________________________                                        *Formula 038                                                                                                 Total                                          % W/W    Ingredients           Quantities                                     ______________________________________                                        6.0      Polyethylene Glycol 8000                                                                            30.0 Gm                                        94.0     Trisodium Citrate, Anhydrous Powder                                                                 470.0 Gm                                       100.0                          500.0 Gm                                       ______________________________________                                    

Blend powders together and then pass them thru a 4" Air Mill(micronizer).

    ______________________________________                                        *Formula 171                                                                                                 Total                                          % W/W    Ingredients           Quantities                                     ______________________________________                                        0.2      Dioctyl Sodium Sulfosuccinate (DOSS)                                                                1.0 Gm                                         99.8     Calcium Sorbate       500.0 Gm                                       100.0                          501.0 Gm                                       ______________________________________                                    

Prepare 200 Gm of 0.5% w/w DOSS from Complemix-50 (50% DOSS) by mixingtogether 2 Gm of Complemix-50 and 198 Gm of water.

Add the calcium sorbate to the pot of a Hobart Tabletop Mixer and addthe 200 Gm of DOSS solution to it while mixing.

With continued mixing add an additional 135 Gm of water.

Discharge the dampened powder and dry it in a hot air oven at 130° F.overnight, (ca. 16 hours).

Pass the dried powder thru a #60 mesh screen.

Example 4

Ibuprofen Swallow Tablet Formulation

    ______________________________________                                        Formula 182                                                                                                Total                                            mg/tab   Ingredients         Quantities                                       ______________________________________                                        792.0    Formula 144*        158.4 Gm                                         60.0     Sodium Starch Glycolate                                                                           12.0 Gm                                          45.0     Formula 038 (see Example 3)                                                                       9.0 Gm                                           14.0     Formula 171 (see Example 3)                                                                       2.8 Gm                                           911.0                        182.2 Gm                                         ______________________________________                                    

Add all ingredients to a bottle, cap it, and mix the contents for 10minutes using a Turbula Mixer.

Compress into tablets using 0.344"×0.700" capsule shaped tooling.

*Formula 144

Pass a quantity of Ibuprofen thru a #24 mesh screen to delump it.

Prepare a powder mixture of 200.0 Gm of Ibuprofen and 400.0 Gm ofTrisodium Citrate, Anhydrous Powder by mixing them together in the potof a Tabletop Hobart Mixer.

Prepare a 400 Gm quantity of 40% w/w solution of Trisodium CitrateDihydrate in Water by dissolving 160 Gm of it in 240 Gm of Water.

With the Hobart Mixer running at slow speed, pour in 338 Gm of the 40%solution all at once, on top of the Ibuprofen and Trisodium Citratemixture.

Continue mixing for 20 minutes.

Discharge and pass thru a #24 mesh screen.

Dry in hot air over at 130° F. overnight, (ca. 16 hours).

Dry size by passing thru a #24 mesh screen.

792 mg of the dried granulation provides 200 mg of Ibuprofen in watersoluble form, and 592 mg of Trisodium Citrate Dihydrate.

Example 5

Ketoprofen Swallow Tablet Formulation

    ______________________________________                                                                     Total                                            mg/tab  Ingredients          Quantities                                       ______________________________________                                        110.0   Formula 118*         22.0 Gm                                          700.0   Formula 169 (see Example 2)                                                                        140.0 Gm                                         60.0    Sodium Starch Glycolate                                                                            12.0 Gm                                          20.0    Crospovidone (Polyplasdone XL)                                                                     4.0 Gm                                           45.0    Formula 038 (see Example 3)                                                                        9.0 Gm                                           14.0    Formula 171 (see Example 3)                                                                        2.8 Gm                                           949.0                        189.8 Gm                                         ______________________________________                                    

Add all ingredients to a bottle, cap it, and mix the contents for 10minutes using a Turbula Mixer.

Compress into tablets using 0.344"×0.700" capsule shaped tooling.

*Formula 118

Weight 2.0 Gm of Decaglycerol Tetraoleate (Caprol 10 G 4 0) into a 140mL beaker. Add 98.0 Gm of water and mix with a Lighnin Mixer until allof the Caprol is dispersed.

Add 50.0 Gm of Ketoprofen and 150.0 Gm of Trisodium Citrate, AnhydrousPowder to a large mortar and pestle, and triturate until well mixed.

Add 85.2 Gm of the Caprol dispersion all at once to the powder mixtureand triturate thoroughly, first forming a sticky paste which begins todry up in a few minutes.

Knead the soft mass with the hands, and when it begins to get crumbly,pass it thru a #24 mesh screen.

Dry in hot air oven at 130° F. overnight, (ca. 16 hours).

Dry size by passing thru a #24 mesh screen.

110 mg of the dried granulation provides 25 mg of Ketoprofen in watersoluble form, and ca. 85 mg of Trisodium Citrate Dihydrate.

Example 6

Ranitidine Swallow Tablet Formulation

    ______________________________________                                                                    Total                                             mg/tab  Ingredients         Quantities                                        ______________________________________                                        Formula 188                                                                   140.0   Formula 181*        28.0 Gm                                           635.0   Formula 169 (see Example 2)                                                                       127.0 Gm                                          135.0   Starch 1500         27.0 Gm                                           5.0     Magnesium Stearate  1.0 Gm                                            5.0     Formula 171 (see Example 3)                                                                       1.0 Gm                                            5.0     Silicon Dioxide (Syloid 244FP)                                                                    1.0 Gm                                            925.0                       185.0 Gm                                          ______________________________________                                        *Formula 181                                                                                           Total                                                % W/W Ingredients        Quantities                                           10.0  Ranitidine Hydrochloride                                                                         50.0 Gm                                              10.0  Calcium Acetate Powder                                                                           50.0 Gm                                              (Trace)                                                                             Mixed Tocopherols  (Trace Amt.)                                         80.0  Mannitol Powder    400.0 Gm                                             100.0                    500.0 Gm                                         

Prepare a 0.1% solution of Covi-Ox T-30P (dried mixed tocopherolconcentrate) in water.

Pass the powders thru a #24 mesh screen to delump.

Add them to the pot of a Hobart Tabletop Mixer, and while mixing add 30Gm of the Covi-Ox Solution.

Pass the wet granulate thru a #24 mesh screen and dry it in a hot airoven at 130° F. overnight, (ca. 16 hours).

Dry size by passing thru a #24 mesh screen.

Example 7

Pseudoephedrine Swallow Tablet Formulation

    ______________________________________                                                                     Total                                            mg/tab  Ingredients          Quantities                                       ______________________________________                                        20.0    Pseudoephedrine Hydrochloride                                                                      4.0 Gm                                           800.0   Formula 169 (see Example 2)                                                                        160.0 Gm                                         240.0   Sodium Bicarbonate, Heat Treated                                                                   48.0 Gm                                          75.0    Sodium Starch Glycolate                                                                            15.0 Gm                                          25.0    Crospovidone (Polyplasdone XL)                                                                     5.0 Gm                                           6.0     Magnesium Stearate   1.2 Gm                                           6.0     Formula 171 (see Example 3)                                                                        1.2 Gm                                           6.0     Silicon Dioxide (Syloid FP)                                                                        1.2 Gm                                           1178.0                       235.6 Gm                                         ______________________________________                                    

Pass all ingredients thru a #24 mesh screen to delump.

Add all ingredients to a bottle, cap it, and mix the contents for 10minutes using a Turbula Mixer.

Compress into tablets using 0.344"×0.750" capsule shaped tooling.

It should be understood that many modifications and variations can bemade in the proportions and components used herein without departingfrom the spirit and scope of the invention, which is solely defined bythe claims.

What is claimed is:
 1. A method of preparing a granulate of a sodiumsalt of an acidic therapeutic drug of limited water solubility for usein dosage forms which require high water solubility, comprising thesteps of:(a) mixing an acidic therapeutic drug of limited watersolubility with anhydrous trisodium citrate to form a dry mixture; (b)adding a near saturated aqueous solution of trisodium citrate to the drymixture to form an overwet granulation mixture; (c) mixing the overwetmixture for a time sufficient to allow the anhydrous trisodium citrateto hydrate, forming a mixture dry enough to granulate; and (d)granulating the hydrated mixture.